Enantioselective Synthesis of Chiral Piperidines via the Stepwise

Mar 11, 2016 - molecules and pharmaceutical drugs.1 Despite significant progress toward the ... tetrahydropyridines via the chiral diphosphine/Cu(I)-c...
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Enantioselective Synthesis of Chiral Piperidines via the Stepwise Dearomatization/Borylation of Pyridines Koji Kubota, Yuta Watanabe, Keiichi Hayama, and Hajime Ito J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01375 • Publication Date (Web): 11 Mar 2016 Downloaded from http://pubs.acs.org on March 14, 2016

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Journal of the American Chemical Society

Enantioselective Synthesis of Chiral Piperidines via the Stepwise Dearomatization/Borylation of Pyridines Koji  Kubota,  Yuta  Watanabe,  Keiichi  Hayama  and  Hajime  Ito*   Division  of  Chemical  Process  Engineering,  Graduate  School  of  Engineering,  Hokkaido  University,  Sapporo,  Hokkaido   060-­‐8628,  Japan.   Supporting  Information  Placeholder hough   the   1,2-­‐borylation   reaction   proceeded   as   anticipat-­‐ ABSTRACT:   We   have   developed   a   novel   approach   for   the   ed,   we   failed   to   isolate   the   desired   product   because   it   de-­‐ synthesis   of   enantioenriched   3-­‐boryl-­‐tetrahydropyridines   composed   during   purification.   We   subsequently   investi-­‐ via   the   copper(I)-­‐catalyzed   regio-­‐,   diastereo-­‐   and   enanti-­‐ gated  the  development  of  an  alternative  stepwise  strategy   oselective   protoborylation   of   1,2-­‐dihydropyridines,   which   involving  the  combination  of  Fowler’s  dearomative  reduc-­‐ were  obtained  by  the  partial  reduction  of  the  pyridine  de-­‐ tion  of  pyridines10  with  the  copper(I)-­‐catalyzed  enantiose-­‐ rivatives.   This   dearomatization/enantioselective   boryla-­‐ lective   borylation   of   the   resulting   unstable   1,2-­‐ tion   stepwise   strategy   provides   facile   access   to   chiral   pi-­‐ dihydropyridines.4   However,   this   novel   method   would   be   peridines   together   with   the   stereospecific   transformation   very  challenging  because  of  the  difficulties  associated  with   of   a   stereogenic   C–B   bond   from   readily   available   starting   controlling  the  regio-­‐,  diastereo-­‐  and  enantioselectivity  for   materials.   Furthermore,   the   utility   of   this   method   was   nitrogen-­‐containing   conjugated   diene   substrates.   Fur-­‐ demonstrated   for   the   concise   synthesis   of   the   antidepres-­‐ thermore,   there   have   been   no   reports   in   the   literature   to   sant   drug   (–)-­‐paroxetine.   A   theoretical   study   of   the   reac-­‐ date   pertaining   to   the   selective   borylation   of   such   com-­‐ tion  mechanism  has  also  been  described.   pounds.11   Herein,   we   report   the   development   of   a   novel   Chiral   piperidines   are   important   structural   motifs   that   method  for  the  enantioselective  synthesis  of  chiral  3-­‐boryl-­‐ can  be  found  in  a  wide  variety  of  naturally  occurring  bioac-­‐ tetrahydropyridines  via  the  chiral  diphosphine/copper(I)-­‐ tive   molecules   and   pharmaceutical   drugs.1   Despite   signifi-­‐ catalyzed   regio-­‐,   diastereo-­‐   and   enantioselective   proto-­‐ cant   progress   towards   the   development   of   synthetic   ap-­‐ borylation   of   1,2-­‐dihydropyridines,   which   were   derived   proaches  capable  of  providing  facile  access  to  these  mole-­‐ from   the   dearomative   reduction   of   readily   available   pyri-­‐ cules,   the   development   of   a   simple,   mild   and   efficient   dines  (Scheme  1a).  Notably,  the  subsequent  derivatization   method   for   the   direct   preparation   of   chiral   piperidines   of   the   boryl   group   in   these   products,   as   well   as   the   re-­‐ remains  highly  desired.  Based  on  the  abundance  of  readily   maining   enamine   moiety,   could   provide   facile   access   to   available   nitrogen-­‐containing   aromatic   compounds,   the   complex   chiral   piperidines   bearing   a   C–3   stereocenter,   enantioselective   dearomatization   of   pyridine   derivatives   which  are  important  components  in  various  pharmaceuti-­‐ represents   a   powerful   and   efficient   method   for   the   for-­‐ cal   drugs   (Scheme   1b).1   In   actual   fact,   the   antidepressant   mation   of   chiral   N-­‐heterocyclic   compounds.   Furthermore,   drug   (–)-­‐paroxetine   was   successfully   synthesized   in   this   the   dearomatization   of   pyridine   derivatives   can   provide   study   using   our   newly   developed   approach.   A   theoretical   direct   access   to   various   saturated   chiral   N-­‐heterocyclic   study  of  the  reaction  mechanism  has  also  been  described.   structures,  making  it  particularly  efficient.2,3  Recently,  sev-­‐ Scheme  1.  (a)   Stepwise   Dearomatization/Enantioselective   eral   strategies   have   been   developed   for   the   dearomatiza-­‐ Borylation   Strategy.   (b)   Representative   Bioactive   Chiral   tion  of  pyridines  involving  either  the  nucleophilic  addition   Piperidines.   of  a  suitable  nucleophile  to  a  pyridinium  salt  or  the  use  of   a) Dearomatization/enantioselective borylation sequence (This work) stepwise  reduction/enantioselective  catalysis.3,4   hydride We  recently  reported  the  first  C–B  bond  forming  enan-­‐ R1 R2 R1 R 2 cat. Cu(I) / L* R1 R 2 source (pin)B–B(pin) tioselective   dearomatization   of   indoles   under   copper(I)   N N N R 3-X alcohol, base B(pin) R3 R3 catalysis  to  give  the  corresponding  chiral  3-­‐boryl-­‐indolines   pyridines conjugated dienes boryl-tetrahydropyridines with   excellent   regio-­‐,   diastereo-­‐   and   enantioselectivity.5-­‐7   highly regio-, stereoselective readily available difficult to control regiostarting materials and stereoselectivity novel chiral building block Transformations   of   this   type   have   great   numerous   poten-­‐ b) Representative chiral piperidine-based bioactive molecules tial   applications   in   synthetic   and   medicinal   chemistry   be-­‐ Ph cause  chiral  N-­‐heterocyclic  organoborons  are  amenable  to   N O N N O Ph N OPh a  wide  variety  of  stereospecific  functionalization  reactions   N OH through   their   stereogenic   C–B   bond.8,9   With   this   in   mind,   N NH 2 ibrutinib we  became  interested  in  the  development  of  an  enantiose-­‐ N O (−)-preclamol O lective   method   for   the   conversion   of   pyridines   to   chiral   F zamifenacine CO 2H boryl-­‐piperidines,   which   could   be   used   as   novel   nucleo-­‐ O N philes  for  the  synthesis  of  piperidine-­‐based  bioactive  com-­‐ N HN O O N N Ph N pounds.9  Our  initial  efforts  focused  on  the  development  of   (−)-paroxetine O KDM2A inhibitor a   direct   C–B   bond   forming   method   using   an   N-­‐acyl   pyri-­‐ dinium   salt   as   the   substrate   under   copper(I)   catalysis   with   The   results   of   an   extensive   optimization   process   re-­‐ the  concomitant  dearomatization  of  the  pyridine  ring.  Alt-­‐ vealed  that  the  reaction  of  methoxycarbonyl-­‐protected  1,2-­‐

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dihydropyridine  2a  (R  =  H),  which  was  isolated  from  pyri-­‐ dine   1a   using   Fowler’s   reduction   method10,   with   bis(pinacolato)diboron   (3)   (1.2   equiv)   in   the   presence   of   CuCl/(R,R)-­‐QuinoxP*  L1   (5  mol  %),  K(O-­‐t-­‐Bu)  (20  mol  %)   and  MeOH  (2.0  equiv)  in  THF  at  –10°C  afforded  the  chiral   3-­‐boryl-­‐tetrahydropyridine  (R)-­‐4a  in  high  yield  with  excel-­‐ lent  enantioselectivity  (Table  1,  entry  1).   Table  1.  Optimization  of  the  Reaction  Conditions.a   R N R = H (1a) R = Ph (1b)

NaBH 4 ClCO 2Me

R

MeOH −78 °C, 1 h

O

N

MeO

R = H (2a) R = Ph (2b)

R

cat. Cu(I) / L* B 2(pin) 2 (3) K(O-t-Bu) alcohol −10 °C, 2 h

O

N

B(pin) MeO R = H [(R)-4a] R = Ph [(R,R)-4b]

entry

R

chiral ligand

Alcohol

d.r.

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 d 11e 12f,g 13 h 14 h

H (2a) H (2a) H (2a) H (2a) H (2a) H (2a) H (2a) H (2a) H (2a) H (2a) H (2a) H (2a) Ph (2b) Ph (2b)

(R,R)-L1 (R,R)-L2 (R,R)-L3 (R)-L4 (R)-L5 (R,R)-L6 (R,S)-L7 (R,R)-L1 (R,R)-L1 (R,R)-L1 (R,R)-L1 (R,R)-L1 (R,R)-L1 (R)-L5

MeOH MeOH MeOH MeOH MeOH MeOH MeOH t-BuOH PhOH MeOH MeOH MeOH MeOH t-BuOH

– – – – – – – – – – – – 99:1 97:3

93 92 82 95%),  with  high  enantioselectivity  (98%  ee).  The  syn  con-­‐ figuration   between   the   boryl   group   and   the   deuterium   atom   at   the   4-­‐position   was   confirmed   by   NOE   analysis.   These  results  therefore  suggested  that  the  current  boryla-­‐ tion   proceeds   via   the   regio-­‐   and   enantioselective   syn-­‐4,3-­‐ addition   of   an   active   borylcopper(I)   to   the   substrate,   fol-­‐ lowed   by   the   stereoretentive   SE2   protonation   of   the   al-­‐ lylcopper(I)  intermediate  by  the  alcohol  additive.17   Density   functional   theory   calculations   (B3PW91/cc-­‐ pVDZ)   were   performed   to   understand   the   unprecedented   regioselectivity   of   this   borylation   process   (Figure   1).   This   reaction   could   potentially   proceed   via   four   different   borylcupration   pathways   (paths   A–D,   Figure   1).   All   of   the   borylation   pathways   were   calculated   using   the   achiral   borylcopper(I)/Me2PCH=CHPMe2   model   complex   with   2a   as   a   substrate.   The   results   showed   that   the   activation   en-­‐ ergies  for  pathways  A  (ΔGTS1)  and  C  (ΔGTS3),  leading  to  the  

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corresponding   stable   allylcopper(I)   intermediates,   were   lower  than  those  of  pathways  B  and  D.  For  pathway  C,  ste-­‐ ric  congestion  between  the  B(pin)  and  carbamate  moieties   would   destabilize   the   complex   during   the   borylcupration   process.18  The   current   borylation   process   would   therefore   most  likely  proceed  via  a  4,3-­‐borylcupration  process  (path   A)  to  form  intermediate  P1  with  high  selectivity.  The  simi-­‐ lar   calculations   in   the   case   of   2b   also   indicated   that   the   activation  energy  for  the  4,3-­‐addition  was  lower  than  tho-­‐ se  of  other  pathways.19   path A

R

4,3-addition R

B(pin)

N

G C1 = +7.7

path B

R

CuL B(pin)

I

G C2 = +8.9

path C

LCu B(pin) II

R (pin)B

N

L = Me 2P R = –CO 2Me

PMe 2

R LCu

CuL

N

B(pin)

G C4 = +9.8

B(pin)

N

CuL G P1 = −11.5

R

CuL

N

B(pin)

B(pin) GTS2 = +21.8

R

Cu L

N

R

CuL

N

(pin)B

G C3 = +9.4

path D

B(pin)

N

GTS1 = +19.0

R

N

N

+

R

CuL

Cu L

GTS3 = +20.4

R

LCu

G P2 = −7.3

R

G P3 = −8.0

R

N

B(pin)

GTS4 = +27.0

N

(pin)B LCu

N

LCu (pin)B G P4 = −0.9

 

Figure   1.   Density   functional   theory   calculations   for   the   four   regioisomeric   pathways   A–D   (B3PW91/cc-­‐pVDZ).   Relative  G  values  (kcal/mol)  at  298  K,  1.0  atom  in  the  Gas   Phase.   In   summary,   we   have   developed   a   novel   stepwise   dearomatization/enantioselective   borylation   strategy   for   the  preparation  of  chiral  3-­‐boryl-­‐tetrahydropyridines  from   pyridines   with   excellent   enantiomeric   purity.   This   reaction   involves   the   unprecedented   regio-­‐   and   enantioselective   borylcupration   of   1,2-­‐dihydropyridines,   followed   by   the   stereoretentive   SE2   protonation   of   the   resulting   al-­‐ lylcopper(I)  intermediates  by  an  alcohol  additive.  The  cur-­‐ rent   methodology   represents   a   simple   and   direct   method   for   the   synthesis   of   optically   active   piperidines   bearing   a   C3-­‐stereocenter   in   combination   with   a   stereospecific   bo-­‐ ron  functionalization  process.  

ASSOCIATED CONTENT Supporting Information Experimental   procedures   and   data.   This   material   is   available   free  of  charge  via  the  Internet  at  http://pubs.acs.org.  

AUTHOR INFORMATION Corresponding Author [email protected]  

Notes The  authors  declare  that  there  are  no  competing  financial   interests.  

ACKNOWLEDGMENTS This   study   was   financially   supported   by   the   MEXT   (Japan)   program   (Strategic   Molecular   and   Materials   Chemistry   through  Innovative  Coupling  Reactions)  of  Hokkaido  Universi-­‐ ty,   as   well   as   the   JSPS   (KAKENHI   Grant   Numbers   15H03804  

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and   15K13633).   K.K.   would   like   to   thank   the   JSPS   for   their   scholarship  funding  (KAKENHI  Grant  Number 14J02341).  

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  Prieto,   A.;   Bonet,   A.;   Diaz-­‐ Requejo,  M.  M.;  Ramirez,  J.;  Pérez,  P.  J.;  Fernández,  E.  Organometallics   2009,  28,  659.  (b)  Lee,  Y.;  Hoveyda,  A.  H.  J.   Am.   Chem.   Soc.  2009,  131,   3160.  (c)  Noh,  D.;  Chea,  H.;  Ju,  J.;  Yun,  J.  Angew.  Chem.,  Int.  Ed.  2009,  48,   6062.  (d)  Lee,  J.  C.  H.;  McDonald,  R.;  Hall,  D.  G.  Nat.  Chem.  2011,  3,  894.   (e)  He,  Z.  T.;  Zhao,  Y.  S.;  Tian,  P.;  Wang,  C.  C.;  Dong,  H.  Q.;  Lin,  G.  Q.   Org.   Lett.   2014,   16,   1426.   (f)   Parra,   A.;   Amenós,   L.;   Guisán-­‐Ceinos,   M.;   López,   A.;   Ruano,   J.   L.   G.;   Tortosa,   M.   J.   Am.   Chem.   Soc.   2014,   136,   15833.     (8)  Boronic  Acids:  Preparation  and  Applications  in  Organic  Synthesis,   Medicine   and   Materials,   2   nd   revised   ed.;   Hall,   D.   G.,   Ed.;   Wiley-­‐VCH:   Weinheim,  2011.     (9)   For   examples   of   the   synthesis   of   chiral   4-­‐boryl-­‐piperidines,   see:   (a)  Lessard,  S.;  Peng,  F.;  Hall,  D.  G.  J.  Am.  Chem.  Soc.  2009,  131,  9612.   (b)  Ding,  J.;  Hall,  D.  G.  Angew.   Chem.,   Int.   Ed.  2013,  52,  8069.  (c)  Ding,   J.;  Rybak,  T.;  Hall,  D.  G.  Nat.  Commun.  2014,  5,  5474.   (10)   Fowler,   F.   W.   J.   Org.   Chem.   1972,   37,   1321.   The   1,2-­‐ dihydropyridines  were  isolated  prior  to  the  next  borylation  step,  but   should  be  used  immediately  in  order  to  prevent  decomposition.   (11)  We  have  reported  the  first  copper(I)-­‐catalyzed  regio-­‐  and  enan-­‐ tioselective   protoborylation   of   carbocyclic   1,3-­‐dienes,   see:   Sasaki,   Y.;   Zhong,  C.;  Sawamura,  M.;  Ito,  H.  J.  Am.  Chem.  Soc.  2010,  132,  1226.   (12)  The  triarylphosphine  type  ligand  showed  high  enough  reactivity   toward   4-­‐aryl-­‐1,2-­‐dihydropyridines   because   an   aryl   group   at   4-­‐ position   could   lower   the   LUMO   levels   of   1,2-­‐dihydropyridines   by   extension   of   the   conjugated   system   in   the   substrate,   which   could   promote  the  insertion  reaction  of  a  borylcopper(I)  intermediate.   (13)  The  results  of  further  investigation  on  the  substrate  scope  have   been  described  in  the  Supporting  Information.   (14)  Bonet,  A.;  Odachowski,  M.;  Leonori,  D.;  Essafi,  S.;  Aggarwal,  V.  K.   Nat.  Chem.  2014,  6,  584.   (15)  Recent  syntheses  of  (–)-­‐paroxetine,  see:  (a)  Hynes,  P.  S.;  Stupple,   P.   A.;   Dixon,   D.   J.  Org.  Lett.   2008,   10,   1389.   (b)   Kim,   M.   –H.;   Park,   Y.;   Jeong,   B.   –S.;   Park,   H.   –G.;   Jew,   S.   –S.   Org.   Lett.   2010,   12,   2826.   (c)   Krautwald,  S.;  Schafroth,  M.  A.;  Sarlah,  D.;  Carreira,  E.  M.  J.  Am.  Chem.   Soc.  2014,   136,   3020.  (d)   White,   N.   A.;   Ozboya,   K.   E.;   Flanigan,   D.   M.;   Rovis,  T.  Asian  J.  Org.  Chem.  2014,  3,  442.     (16)  Sadhu,  K.  M.;  Matteson,  D.  S.  Organometallics  1985,  4,  1687.   (17)  The  reaction  pathway  is  proposed  in  the  Supporting  Information.   (18)   DFT   calculations   also   suggest   that   the   electronic   properties   of   dienes   would   be   important   for   high   regioselectivity.   The   details   and   calculated  structures  are  included  in  the  Supporting  Information.     (19)   The   details   of   the   calculations   are   included   in   the   Supporting   Information.  

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  hydride R 2 source

R1 N

ClCO 2R 3

R1 O R 3O

R2 N

cat. Cu/L* B 2(pin) 2 K(O-t-Bu) alcohol

R2

R1 O

N

B(pin)

R 3O

Unprecedented regio-, diastereo- and enantioselective Readily available starting materials Chiral boryl-tetrahydropyridines: Novel building blocks

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